Oligonucleotide compositions and methods thereof

Patent metadata

Field	Value
Publication number	US-10450568-B2
Application number	US-201816139091-A
Country	US
Kind code	B2
Filing date	Sep 23, 2018
Priority date	Oct 9, 2015
Publication date	Oct 22, 2019
Grant date	Oct 22, 2019

Abstract

Among other things, the present disclosure relates to designed oligonucleotides, compositions, and methods thereof. In some embodiments, provided oligonucleotide compositions provide altered splicing of a transcript. In some embodiments, provided oligonucleotide compositions have low toxicity. In some embodiments, provided oligonucleotide compositions provide improved protein binding profiles. In some embodiments, provided oligonucleotide compositions have improved delivery. In some embodiments, provided oligonucleotide compositions have improved uptake. In some embodiments, the present disclosure provides methods for treatment of diseases using provided oligonucleotide compositions.

First claim

The invention claimed is:

1. An oligonucleotide having the structure of:
fU*SfC*SfA*SfA*SfG*SfG*SmAfA*SmGmA*SfU*SmGmGfC*SfA*Sf*SfU*SfU*SfU*SfC*SfU (SEQ ID NO: 773),

or a pharmaceutically acceptable salt thereof, wherein:
f represents a 2′-F modification to a nucleoside;
S represents a Sp phosphorothioate; and
m represents a 2′-OMe modification to a nucleoside.

2. The oligonucleotide of claim 1 , wherein the oligonucleotide is in a salt form.

3. The oligonucleotide of claim 1 , wherein the salt form is a sodium salt.

4. An oligonucleotide, wherein the oligonucleotide is a sodium salt of:
fU*SfC*SfA*SfA*SfG*SfG*SmAfA*SmGmA*SfU*SmGmGfC*SfA*SfU*SfU*SfU*SfC*SfU (SEQ ID NO: 773), wherein:
f represents a 2′-F modification to a nucleotide;
*S represents Sp phosphorothioate;
m represents a 2′-OMe modification to a nucleoside; and
the number of sodium ions in the sodium salt equals the total number of phosphorothioate and phosphate linkages in the oligonucleotide.

5. A chirally controlled composition of an oligonucleotide having the structure of:
fU*SfC*SfA*SfA*SfG*SfG*SmAfA*SmGmA*SfU*SmGmGfC*SfA*SfU*SfU*SfU*SfC*SfU (SEQ ID NO: 773), or a pharmaceutically acceptable salt thereof, wherein:
f represents a 2′-F modification to a nucleoside;
*S represents a Sp phosphorothioate; and
m represents a 2′-OMe modification to a nucleoside,
wherein the composition is enriched, relative to a substantially racemic preparation of the oligonucleotide, for the oligonucleotide.

6. A pharmaceutical composition, comprising a therapeutically effective amount of an oligonucleotide and at least one pharmaceutically acceptable inactive ingredient selected from pharmaceutically acceptable diluents, pharmaceutically acceptable excipients, and pharmaceutically acceptable carriers, wherein the oligonucleotide has the structure of:
fU*SfC*SfA*SfA*SfG*SfG*SmAfA*SmGmA*SfU*SmGmGfC*SfA*SfU*SfU*SfU*SfC*SfU (SEQ ID NO: 773), or pharmaceutically acceptable salt thereof, wherein:
f represents a 2′-F modification to a nucleoside;
*S represents a Sp phosphorothioate; and
m represents a 2′-OMe modification to a nucleoside.

7. The pharmaceutical composition of claim 6 , wherein the pharmaceutical composition is a solution.

8. The composition of claim 5 , wherein the oligonucleotide is in a salt form.

9. The composition of claim 5 , wherein the oligonucleotide is a sodium salt.

10. The composition of claim 9 , wherein the number of sodium ions in the sodium salt equals the total number of phosphorothioate and phosphate linkages in the oligonucleotide.

11. The composition of claim 6 , wherein the oligonucleotide is in a salt form.

12. The composition of claim 6 , wherein the oligonucleotide is a sodium salt.

13. The composition of claim 12 , wherein the number of sodium ions in the sodium salt equals the total number of phosphorothioate and phosphate linkages in the oligonucleotide.

Assignees

• Wave Life Sciences Ltd

Inventors

• Butler David Charles Donnell
• Divakaramenon Sethumadhavan
• Francis Christopher J
• Frank-Kamenetsky Maria David
• Iwamoto Naoki
• Lu Genliang
• Marappan Subramanian
• Meena
• Vargeese Chandra
• Verdine Gregory L
• Yang Hailin
• Zhang Jason Jingxin

Classifications

• C12N15/113 Primary

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title

• C12N2320/33

  Alteration of splicing · CPC title

• C12N2310/346

  having a combination of backbone and sugar modifications · CPC title

• C12N2310/343

  having patterns, e.g. ==--==--==-- · CPC title

• C12N2310/322

  2'-R Modification · CPC title